Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorpha n (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme C YP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phen otype on DEM antinociceptive and neuromodulatory effects. Using a randomize d, double-blind, crossover, placebo-controlled design, healthy volunteers ( n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharma codynamics were assessed for their antinociceptive and neuromodulatory effe cts. Antinociceptive effects were assessed over 4 h by subjective pain thre shold and RIII nociceptive reflex (RIII) monitoring, Neuromodulatory effect s were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2 D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. in poor metabolizer s, DEM induced a significant increase in objective (+45%) and subjective (35%) pain thresholds, in extensive metabolizers, only a slight and shortlas ting increase in the subjective threshold was observed, whereas no effect w as seen on the objective threshold. DEM modulates secondary hyperalgesia co mpared with DOR. The CYP2D6 phenotype affects the disposition of DEM and th e production of the active metabolite DOR. The impact of the CYP2D6 phenoty pe is of major importance for the spinal antinociceptive and neuromodulator y effects of DEM.